5-(3-substituted amino-2-hydroxypropoxy)-1,3-disubstituted pyrazoles and method of preparation

ABSTRACT

5-(3-Substituted amino-2-hydroxypropoxy)-1,3-disubstituted pyrazoles possessing Beta -adrenergic blocking properties are described. Products are prepared by reaction of the 1,3disubstituted-1,2-pyrazol-5-one with an epihalohydrin and the epoxide formed reacted with the appropriate substituted amine.

United States Patent Wasson et al.

5-( 3-SUBSTITUTED AMINO-2-HYDROXYPROPOXY)-1,3- DISUBSTITUTED PYRAZOLESAND METHOD OF PREPARATION Inventors: Burton Kendall Wasson, \j alois;

Clarence Stanley Rooney, Beaconsfield, both of Canada Merck Sharp &Dohme (I.A.), Rahway, NJ.

Filed: Nov. 6, 1974 Appl. No.: 521,416

Related US. Application Data Continuation of Ser. No. 341,446, March 15,1973, abandoned.

Assignee:

Foreign Application Priority Data May 5, 1972 Canada 141470 US. Cl.260/310 R; 424/273 Int. Cl. C07D 231/20 Field of Search 260/310 RReferences Cited UNITED STATES PATENTS 12/1971 Gschwend 260/310 R OTHERPUBLICATIONS Crowther et al., Chemical Abstracts, Vol. 76: 14874 1 g(1972).

Petrow et a1., Chemical Abstracts Vol. 51, Columns 2662-2663, (1957).

Sandoz, Chemical Abstracts, Vol. 66:18669x (1967).

Shapiro et a1., Chemical Abstracts, Vol, 58, Column 1476, (1963).

Primary ExaminerDonald B. Moyer Attorney, Agent, or FirmDanie1 T. Szura;J. Jerome Behan [5 7] ABSTRACT 5-( 3-Substituted amino-2-hydroxypropoxy)-1 ,3- disubstituted pyrazoles possessing ,B-adrenergic blockingproperties are described. Products are prepared by reaction of thel,3-disubstituted l ,2-pyrazol-5-one with an epihalohydrin and theepoxide formed reacted with the appropriate substituted amine.

4 Claims, No Drawings -(3-SUBSTITUTED AMINO-Z-I'IYDROXYPROPOXY1,3-DISUB- STITUTED PYRAZOLES AND METHOD OF PREPARATION This is a cont.of application Serial No. 341,446 filed March 15, I973 now abandoned.

This invention is concerned with 5-(3-substitutedamino-2-hydroxypropoxy)-l ,3-disubstituted' pyrazole compounds whichexhibit B-adrenergic blocking properties.

The novel pyrazole compounds of this invention have the structure andpharmacologically acceptable salts thereof wherein R representshydrogen, C alkyl, C alkoxy, phenyl or benzyl; R represents C-cycloalkyl, phenyl- C alkyl, phenyl, substituted phenyl wherein thesubstituent(s) is (are) similar or dissimilar selected from halo(especially chloro, bromo, fluoro), C, alkyl, C alkoxy', and Rrepresents a straight or branched chain C alkyl, a straight or branchedchain hydroxy substituted C alkyl, or a straight or branched chain Calkinyl group, phenyl-C alkyl and indolyl-C alkyl.

Suitable pharmacologically acceptable salts of product l are acidaddition salts derived from inorganic acids for example hydrochlorides,hydrobromides, phosphates, or sulfates or salts derived from organicacids, for example, oxalates, lactates, malates, maleates, formates,acetates, succinates, tartrates, salicylates, citrates, phenylacetates,benzoates, p-toluenesulfonates and other salts such as those thatprovide relatively insoluble products that afford a slow release of theactive material, for example, a 1,]-methylenebis(2-hydroxy-3-naphthoate) and the like.

The novel compounds, I, as well as their intermediates which contain oneasymmetric carbon atom in the propylene chain will be obtained as aracemic mixture which can be separated into optically active isomers byknown methods, for example, by forming a salt with an optically activeacid, many of which are known to those skilled in the art, such asoptically active tartaric, mandelic, cholic, 0,0-di-p-toluoyl tartaric,0,0-di-benzoyl 2 tartaric acids or other acids conventionally employedfor this purpose.

The potential of a product as a B-adrenergic blocking agentconventionally is evaluated by the protocol which was employed to assessthe B-blocking properties of the novel compounds of this invention. Theprotocol employed comprises intravenous administration of graded dose sof the selected compound to rats which then are challenged with astandard dose of isoproterenol, a product known to be a B-stimulant.

The clinical application of B-adrenergic blocking agents is well knownto physicians. Uses for the novel compounds of this invention includetreatment of angina pectoris, catecholamine induced cardiac arrhythmiasand hypertension as well as for the control of tachycardia that may bedrug induced (as by isoproterenol) or brought about by physiologicalconditions. In view of the considerable amount of literature that hasaccumulated concerning the use of B-adrenergic blocking agents,physicians would employ the products of this invention in any of theknown conditions where a B- blocker is needed, such as in the managementof angina pectoris.

The products can be prepared in pharmaceutical formulations suitable fororal or parenteral administration preferably in the form of tablets,solutions, suspensions, or emulsions using well known techniques andexcipients, diluents, lubricants, and the like. Dosage units of fromabout 1 mg. to about 40 mgs. can be provided for thesymptomatiti'adjustment of dosage by the physician depending upon theage and condition of the patient.

The novel pyrazole products, I, of this invention advantageously can beprepared by the synthesis schematically illustrated below:

The l,3-disubstituted-l,2-pyrazolin-5-one (II) is treated withepichlorhydrin or epibromhydrin (III) to give the epoxide (.IV). Thereaction is facilitated by the presence of 'atrace of base which servesas a catalyst, preferably piperidine, piperidine hydrochloride,pyridine, or other heterocyclic N-containing bases followed by shakingthe crude product with aqueous alkali metal hydroxide. Ideally theepihalohydrin is used in excess for its solvent properties and thereaction proceeds at room temperature or with heating up to about C.Treatment of the epoxide (IV) with the amine, H NR provides the desiredpyrazole product I. Advantageously an excess of the amine is employedfor its solvent properties, from 3 to 5 moles of the amine beingadequate to give very good yields of the desired product. This step canbe carried out at a temperature between about ambient temperature andreflux although it is preferred to use some heating of the reactionmixture.

The following examples will illustrate representative products of thisinvention prepared by the above described procedure. The followingexamples however are not to be considered as limiting the preparation ofany particular compound to the method described in the exampleswhich areprovided solely to illustrate the best mode currently known toapplicants for the preparation of the novel pyrazole products of thisinvention.

EXAMPLE 1-(3-tert-butylarnino-2-hydroxypropoxy)-3-methyl-lphenylpyrazoledihydrochloride methanolate A mixture of3-methyl-l-phenyl-1,2-pyrazolin-5-one (5.22 g., 30 mmoles),epichlorhydrin (16.6 g., 180 mmoles) and two drops of piperidine arewarmed at 110 C. for 1.5 hours. The mixture was evaporated in vacuo,dissolved in benzene and again evaporated to dryness. The resulting oilyproduct is shaken one-half hour with sodium hydroxide solution (45 ml.,33%). The mixture is extracted with chloroform, the chloroform extractswashed with water and evaporated to dryness. The residue is dissolved inchloroform and chromatographed on silica gel to afford5-(2,3-epoxypropoxy)-3-methyl-l-phenylpyrazole (2.6 g.). The crudeepoxide is refluxed overnight with tert-butylamine (12 ml.) andevaporated to dryness. The residue is dissolved in benzene, extractedwith 2N HC1 and the aqueous acid solution evaporated .to dryness. Theresidue is crystallized several times from a mixture of methanol andethyl acetate to give 1.98 g. of5-(3-tertbutylamino-2-hydroxypropoxy)-3-methyl-l-phenylpyrazoledihydrochloride methanolate, m.p. 195-197.5 C.

Analysis calculated for C H O N .2HCLCH OH:

Found: N, 9.82; Cl, 17.07.

EXAMPLE 2 5-( 3-Isopropylamino-2-hydroxypropoxy)-3-ethyl-1phenylpyrazole -By replacing the 3-methyl-1-phenyl-l,2-pyrazolin- 5-onea'nd the tert-butylamine employed in Example 1 by equivalent quantitiesof 3-ethyl-l-p he nyl-l,2- pyrazolin-5-one and isopropylamine,respectively, and following substantially the same procedure describedin Example 1 there is obtained 5-(3-isopropylamino-2-hydroxypropoxy)-3-ethyll -phenylpyrazole.

EXAMPLE 3 5 -(3-lsopropylamino-Z-hydroxypropoxy)-3-ethoxy-1-phenylpyrazole By replacing the 3-methyl-1-phenyl-l,2-pyrazolin- 5-oneand the tert-butylamine employed in Example 1 4 by equivalent quantitiesof 3-ethoxy-1-phenyl-l,2- pyrazolin-S-one and isopropylamine,respectively, and following substantially the same procedure describedin Example 1 there is obtained 5-(3-isopropylamino-2-hydroxypropoxy)-3-ethoxyl -phenylpyrazole.

EXAMPLE 4 5-[ 3-( 2 ,2-Dimethylpropylamino )-2-hydroxypropoxy 3-ethoxyl-phenylpyrazole By replacing the 3-methyl-l-phenyl-1,2-pyrazolin- 5-oneand the tert-butylamine employed in Example 1 by equivalent quantitiesof 3-ethoxy-1-phenyl-l,2- pyrazolin-S-one and 2,2-dimethylpropylamine,respectively, and following substantially the same procedure describedin Example 1 there is obtained 5-[3-(2,2-dimethylpropylamino)-2-hydroxypropoxy]-3-ethoxyl-phenylpyrazole.

EXAMPLE 5 5-[3-( l ,1-dimethylpropargylamino)-2-hydroxypropoxy]-3-ethoxyl -phenylpyrazole By replacing the3-methyl-l-phenyl-l,2-pyrazolin- 5-one and the tert-butylamine employedin Example 1 by equivalent quantities of 3-ethoxy-l-phenyl-l,2-pyrazolin-S-one and l,l-dimethylpropargylamine, respectively, andfollowing substantially the same procedure described in Example 1 thereis obtained 5-[3- l ,1-dimethylpropargylamino)-2-hydroxypropoxy]-3-ethoxy- 1 -phenylpyrazole.

EXAMPLE 6 5-[ 3-( 1,1-dimethyl-2-hydroxyethylamino)-2-hydroxypropoxy]-3-ethyl- 1 -phenylpyrazole By replacing the3-methyl-l-phenyl-1,2-pyrazolin- 5-one and the tert-butylamine employedin Example 1 quantities of 3-ethyl-l-phenyl-l,2- pyrazolin-S-one l, l-dimethyl-2-hydroxyethylamine, respectively, and following substantiallythe same procedure described in Example 1 there is obtained 5- [3-( l,1-dimethyl-2-hydroxyethylamino)-2-hydroxypropoxy]-3-ethyl-l-phenylpyrazole.

by equivalent and EXAMPLE 7 Example 1 employing the reactantsidentified.

TABLE I CH CHCH -Cl -OCH CH-CH piperidine Ex. I: H NR -OCH CHCH NHR Ex.No. R R R 8 methyl cyclohexyl t-butyl 9 methyl benzyl t-butyl l methylp-chlorophenyl t-butyl l l methyl p-methoxyphenyl t-butyl l2 methyl2-chloro-4-methoxyt-butyl phenyl l3 n-propyl phenyl t-butyl l4 i-propylphen yl l -methyl-2-phenethyl l5 n-propoxy phenyl l-methyl-Z-phenethyl l6 i-propoxy phenyl t-butyl phenyl phenyl l-methyl-2-(3-indolyl)- l7ethyl l8 Z-phenethyl phenyl t-butyl 19 H phenyl t-butyl 20 methyl phenyll,l-dimethyl-2phenethyl 2] methyl phenyl l,l -dimethyl-2-(3-indolyl)ethyl 22 methyl phenyl 2.2-dimethyl-2-(3-indolyl)ethyl moietyis from 1 to 3 carbon atoms, phenyl, monoor We clalmz' l. A compound ofthe formula and pharmacologically acceptable salts thereof wherein R isselected from the group consisting of hydrogen, alkyl of from 1 to 3carbon atoms, alkoxy of from 1 to 3 carbon atoms, phenyl and benzyl; Ris selected from the group consisting of cycloalkyl of from 3 to 6carbon atoms, phenyl-alkyl wherein the alkyl di-substituted phenylwherein the substituent is chloro, alkyl of from l to 3 carbon atoms,alkoxy of from I to 3 carbon atoms, or mixtures thereof; and R isselected from the group consisting of a straight or branched chain alkylof from*3fto 6 carbon atoms, a straight or branched chain hydroxysubstituted alkyl of from 3 to 6 carbon atoms, a straight or branchedchain alkinyl of from 3 to 6 carbon atoms, phenyl-alkyl the alkyl moietyof from 1 to 6 carbon atoms, and (3-indolyl)-alkyl wherein the alkylmoiety is from 1 to 6 carbon atoms. 2. A compound of claim 1 wherein Ris alkyl of from 1 to 3 carbon atoms and R isstraight or branched chainalkyl of from 3 to 6 carbon atoms.

3. A compound of claim 2 wherein R is phenyl. 4.5-(3-tert-butylamino-2-hydroxypropoxy)-3-methyll -phenylpyrazole.

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 wherein R is alkylof from 1 to 3 carbon atoms and R2 is straight or branched chain alkylof from 3 to 6 carbon atoms.
 3. A compound of claim 2 wherein R1 isphenyl. 4.5-(3-tert-butylamino-2-hydroxypropoxy)-3-methyl-1-phenylpyrazole.